N-trityl-imidazoles for treating fungal infections

ABSTRACT

N-TRITYL-IMIDAZOLES AND SALTS THEREOF OF THE FORMULA: WHEREIN R, R1 AND R2 ARE HYDROGEN, LOWER ALKYL OR PHENYL, OR R1 AND R2 TOGETHER FORM AN ANNULATED BENZENE RING, X,X&#39;&#39; AND X&#34; ARE ALKYL OF 1 TO 12 CARBON ATOMS OR AN ELECTRO-NEGATIVE MOIETY, AND N, N&#39;&#39; ARE AN INTEGER FROM 0 TO 2, OR PHARMACEUTICALLY ACCEPTABLE A ACID SALTS THEREOF MAY BE PRODUCED BY REACTING A SILVER SALT OR ALKALI METAL SALT OF AN IMIDAZOLE OF THE FORMULA:   2-R,4-R&#39;&#39;,5-R2-IMIDAZOLE   WITH A TRITYL HALIDE OF THE FORMULA:   (X)N,(((X&#39;&#39;)N-PHENYL)-C(-HAL)(-(PHENYLENE)-(X&#34;)N&#34;)-)BENZENE   WHEREIN THE SUBSTITUENTS ARE AS ABOVE DEFINED AND HAL IS HALOGEN. THESE COMPOUNDS ARE USEFUL AS ANTIMYCOTICS.   1-(((X)N-PHENYL)-C(-(PHENYLENE)-(X&#34;)N&#34;)(-(PHENYLENE)-   (X&#39;&#39;)N&#39;&#39;)-),2-R,4-R1,5-R2-IMIDAZOLE

United States Patent Office 3,657,442 N-TRITYL-IMIDAZOLES FOR TREATINGFUN GAL INFECTIONS Karl H. Buchel, Leverkusen, and Erik Regel andManfred Plempel, Wuppertal-Elberfeld, Germany, assignors toFarbenfabriken Bayer Aktiengesellschaft, Leverkusen, Germany No Drawing.Original application Sept. 9, 1968, Ser. No. 758,594. Divided and thisapplication May 11, 1970, Ser. No. 36,394 Claims priority, applicationGermany, Sept. 15, 1967, F 53,504 Int. Cl. A61k 27/00 US. Cl. 424-273 4Claims ABSTRACT OF THE DISCLOSURE N-trityl-imidazoles and salts thereofof the formula:

or pharmaceutically acceptable acid salts thereof may be produced byreacting a silver salt or alkali metal salt of an imidazole of theformula:

with a trityl halide of the formula:

Hal Xu' wherein the substituents are as above defined and Hal ishalogen. These compounds are useful as antimycotics.

This application is a division of our co-pending application Ser. No.758,594, filled Sept. 9, 1968.

The present invention is concerned with N-tritylimidazoles and saltsthereof and the production of such compounds. More particularly, thepresent invention is con- 3,657,442 Patented Apr. 18, 1972 cered withN-trityl-imidazoles and salts thereof of the formula:

wherein R, R and R are hydrogen, lower alkyl or phenyl, or R and Rtogether form an annulated benzene ring,

X, X and X" are alkyl of 1 to 12 carbon atoms or an electro-negativemoiety, and

n, n and n" are an integer from O to 2,

or pharmaceutically acceptable acid salts thereof. When R, R or R arealkyl moieties, those having 1 to 4 carbon atoms are preferred. When X,X or X" is an alkyl moiety, it is prefered that such have '1 to 12carbon atoms and such moieties having 1 to 4 carbon atoms are especiallypreferred. Electro-negative substituents which are particularlypreferred are the halogens, i.e., fluorine, chlorine, bromine andiodine, N0 CF CN, as Well as S-lower alkyl and O-lower alkyl; it ispreferred that the alkyl moieties have 1 to 4 carbon atoms. The termalkyl and lower alkyl comprises straight chain as well as branched chainalkyl moieties and also include those containing a double bond.

The salts of the N-trityl-imidazoles (I) are the pharmaceuticallyacceptable non-toxic acid salts. Examples of suitable acids are thehydrohalic acids (hydrochloric being particularly preferred), phosphoricacid, monoand bifunctional carboxylic acids, such as acetic acid,propionic acid, maleic acid, succinic acid, fumaric acid, tartaric acid,citric acid, salicylic acid, sorbic acid, lactic acid and 1,5-naphthalene-disulphonic acid. The hydrohalides, especially thehydrochlorides, lactates and salicylates are of particular 'value.

In a particularly preferred embodiment of the present invention, theN-trityl-imidazoles have the formula:

XGw (11) (Ha) wherein X, X' and X" are alkyl of 1 to 12 carbon atoms orelectro-negative substituents and n, n and n" are 1 or 2.

. Wtih regard to Formula Ila, particularly preferred substituent valuesare those Where X" is fluorine, chlorine, bromine, iodine, N0 CF CN, SCHOCH and n" is l.

The compounds of the present invention can be prepared according totechniques per se known, such as 'by reacting silver salts or alkalimetal salts, in particular the potassium salts of imidazoles of theFormula III with trityl halides of the Formula IV:

(III) X4" wherein R, R and R X, X and X" and n, n and n" have the abovemeanings and Hal is chlorine, bromine or iodine, in an inert solventsuch as benzene, toluene, hexane, cyclohexane or diethyl ether, at atemperature of from about 20 C. to about 100 C. [cf. Chem. Ber. 92, 92(1959); 93, 570 (1960)].

The compounds of the present invention can also be prepared according totechniques per se known by reacting irnidazole derivatives of theFormula -III with tritylcarbinols (cf. the reaction of the carbinolcorresponding to the halide IV with secondary amines). In this case, theirnidazole is generally used in an excess of up to about 100%. If theprocess is carried out under pressure, molar amounts may be used.Furthermore, it may be expedient to carry out the elimination of waterazeotropically in the presence of a high boiling inert organic solvent,such as xylene, chlorobenzenes and the like, at the boiling point of thesolvent used. In the absence of solvents, the process is carried out ata temperature range of from about 140 C. to about 230 C. and preferablyfrom about 170 C. to about 190 C.

It may further be expedient to facilitate the elimination of water byworking in the presence of dehydrating agents, such as e.g. alkalineearth metal oxides (MgO, BaO, CaO) and of A1 approximately molar amountsbeing generally used, but possibly also an excess of up to about 2-3moles.

The following table gives the constants of some N-tritylimidazoles (I,II) by way of example:

M.P., C. (a) l-(trisphenyl-methyl)-imidazole 226-227 (b)l-(trisphenyl-methyl)-2-methyl-irnidazole 225 (c)1-(trisphenyl-methyl)-2,4-dimethyl-imidazole 232 (d)l-(trisphenyl-methyl)-4,5-diphenylirnidazole 228-230 (e)1-(p-chlorophenyl-diphenyl-methyl)-imidazole 140 (f)1-(p-fluorophenyl-diphenyl-methyl)-imidazole 145 (g)1-(tolyl-diphenyl-methyl)-imidazole 128 (h)l-(trisphenyl-methyl)-benzimidazole 180-181 (i)1-(o-chlorophenyl-diphenyl-methyl)- irnidazole 147-149 (j)1-(m-chlorophenyl-diphenyl-methyl)-imidazole 114 (k)1-(p-bromophenyl-diphenyl-methyl)-imidazole 152 (l)1-(o-fiuorophenyl-diphenyl-methyl)-imidazole 185 (m)1-(m-fiuorophenyl-diphenyl-methyl)-imidazole 174 (n)1-(p-nitrophenyl-diphenyl-methyl)- irnidazole 160-170 (0)1-(m-trifluoromethylphenyl-diphenylmethyl) -imidazole 6 (p)1-(p-cyanophenyl-diphenyl-methyl)-imidazole 164 (q)1-(o-methoxyphenyl-diphenyl-methyl)- methyl)-imidazole (x)1-(m-cyanophenyl-diphenyl-methyl)-imidazole 119 (y)1-(o-cyanophenyl-diphenyl-methyl) irnidazole EXAMPLE OF PREPARATION 1-[p-chlorophenyl-diphenyl-methyl] -imadazole (e) 1 mole p-chlorophenyldiphenyl methyl carbinol is mixed with about 2 moles imidazole and themixture is heated, without a solvent, at about 180 C. for 5 hours. Aftercooling, the reaction product is reprecipitated from xylene in order toremove the excess irnidazole. After another reprecipitation from benzenelight petrol, the pure l-[p-chlorophenyl diphenyl methyl] irnidazole isobtained.

M.P. 140-143 C.; yield 53% of theory.

The same compound can also be obtained, when finely powdered silver saltof irnidazole is suspended with the equimolar amount ofp-chlorophenyl-diphenyl-methyl chloride in absolute benzene, the mixtureis heated with stirring and with the exclusion of light at boilingtemperature for about 3 hours, the precipitated silver chloride issubsequently filtered off and the residue remaining after removal of thesolvent is recrystallised from benzene/ light petrol.

By analogous procedure, l-(tris-phenyl-methyl)-imidazole is producedfrom 1-tris-phenyl-methyl-carbinol and imidazole and1-(p-tolyl-diphenyl)-irnidazole is produced from1-p-tolyl-diphenyl-methyl-carbinol and irnidazole.

The other compounds (I, II) can also be obtained according to the aboveprocesses. The conversion of the free compounds into the salts islikewise carried out in known manner.

SALTS OF TRITYL-IMIDAZOLES N-triphenyl-methyl-imidazolium lactate 31 g.N-trityl-imidazole are dissolved by heating in acetonitrile and 10 g.(0.11 mole) d,l-lactic acid are subsequently added. The residueremaining after distilling off the solvent is caused to crystallise bycovering it with ether, the crystallisation product is washed with etherand dried. Yield 40 g. of a colourless crystalline powder of M.P.170-180 C.

N-triphenyl-methyl-imidazolium chloride 31 g. N-trityl-imidazole aredissolved in 400 ml. carbon tetrachloride, and hydrogen chloride issubsequently passed into the solution at room temperature. Thehydrochloride is precipitated after some time and filtered off withsuction. Colourless crystals of M.P. C. after recrystallisation fromacetone/ether 1:1. Yield 33 g.

The following salts are obtained in an analogous manner:

1- (p-chlorophen 1551213251:

um-salicylate oil 1-(n1-chlorophenyl-diphenyl-methyl) imidazoliumhydrochloride 153 1-(o-chlorophenyl-diphenyl-methyl)imidazolium-chloride 159 l-(p-fluorophenyl-diphenyl-methyl)imidazolium-chloride 1 l0 l-(p-fluorophenyl-diphenyl-methyl)imidazolium-lactate 95 1-(o-fiuorophenyl-diphenyl-methyl)imidazoliurn-lactate 1 1-(m-fiuorophenyl-diphenyl-methyl)imidazolium-lactate 120 1-(p-fiuorophenyl-diphenyl-methyl)imidazolium-salicylate 80 1-(p-cyanophenyl-diphenyl-methyl)imidazolium-chloride 147 1-(o-cyanophenyl-diphenyl-methyl)imidazoliurn-chloride 131 1-(p-cyanophenyl-dipheny1-methyl)imidazoliurn-lactate 90 The previously known antimycotics are effectiveeither only against yeasts, such as e.g. Amphotericin B, or only againsthyphomycetes, such as eg Griseofulvin.

In contrast thereto and surprisingly, the compounds (I, II) and theirsalts are effective against hyphomycetes as well as against yeast, evenin the case of oral administration. It is another advantage that thecompounds according to the invention are well tolerated by warm-bloodedanimals.

The compounds can be used as antimycotics, inter alia, in the form of anaqueous emulsion, suspension or solution which can be administered peros. It is also possible to use aqueous solutions of the new salts of thesaid compounds (I).

THERAPEUTIC EFFECT (1) In vitro-effect against human-pathogenic fungiFungistatic Minimum inhibiting concentration as 'y/rnl.

Without serum With serum (1) Trich. asteroides (2) Trich. crateriforme(3) T1ich.equinum (NL) Trich. equinum, woolly (Hoechst) Trich. equt'num,gran. (Hoechst) Trich. tonsurans Trich. verrucosum. Trich. granulosttm.Trich. interdigitale.

95 opl- HHHHHHHHr-HHHHHHHHHHH (l8) Microsp. gallz'nae (19) Microsp.felineum (20) Aspergz'llus m'ger (21) Fen. c0mune (22) Mucor muceda.(23) Blakesleatrispora- (24) Cami. albicans 1 40-1 1 Fungistase.

(2) Effect in vivo (a) Experimental candidosis in white mice: In thecase of oral administration, curative effects can be achieved with dailydoses of 2-3 times 0.5-1 mg./mouse/ day.

(b) Experimental trichophytia in mice caused by Trich. quinckeanum:Development of the infection is prevented by daily doses of 1-2 times1-2 mg./mouse orally.

(0) Experimental trichophytia in guinea pigs caused by T rich. ment.When 15-30 mg. are administered twice Trich. quinokeanum: Development ofthe infection isbizi per os to guinea pigs Weighing 40 grams, areproducible effect on the course of the infection and rapid healing ofthe mycotic lesions is found.

Equally eflective results are produced when other compounds within thescope of (I) or salts of compounds within the scope of (I) andspecifically salts of compounds (a), '(e), (f), (g), (i) and (p) areused. Compounds which are unsubstituted in the imidazole ring may besubstituted in one phenyl group by a halogen atom, preferably chlorineor fluorine in the 0-, mor p-position; such compounds and their saltswith hydrochloric acid, lactic acid or salicylic acid are particularlyuesful. The following usages and dosage ranges are used for thecompounds of the present invention.

(a) For use with humans:

(1) dermatomycoses, caused by fungi of the species Trichophytes,,Microsporium, Epidermophytes, Aspergillus, Candida albicans and otheryeasts;

(2) organomycoses caused by yeasts, mould fungi and dermatophytes;

(b) For veterinary use:

Dermatomycoses and organomycoses caused by yeasts,

mould fungi and dermatophytes.

The compounds of the present invention are administered orally orparenterally as well as locally in the form of solutions, e.g., alcohol,preferably ethanol and isopropanol, buffer solutions, powders, tablets.

The dosage range for humans is in the range of from about 20 to about100 mg./kg. and preferably from about 40 to about 60 mg./ kg.Administration is generally recommended at intervals of about 12 hoursand such administration should be continued for from about 10 to about'60 days.

Nevertheless it may sometimes be necessary to digress from the aforesaidamounts, dependent on the method of administration or also on account ofindividual reactions to the medicine or on the type of its formulationand the moment in time or the intervals at which it is administered. Insome cases, it may be sufficient to use less than the minimum amountstated above, whereas in other cases it may be necessary to go beyondthe stated upper limit. If larger amounts are applied, it may beadvisable to distribute these over a day in several individual doses.

The compounds of the present invention can be used either as such or incombination with pharmaceutically acceptable carriers. Suitable formsfor administration in combination with various inert carriers aretablets, capsules, powders, sprays, aqueous suspensions, injectablesolutions, elixirs, syrups and the like. Carriers of this type comprisesolid extenders or fillers, a sterile aqueous medium as well as variousnon-toxic organic solvents and the like. Obviously, the tablets and thelike suitable for oral administration can be provided with an additionof saccharin or a similar additive. In the aforesaid case, thetherapeutically active compound should be present in the total mixtureat a concentration of about 0.5 to percent by weight, i.e., inquantities which suffice to attain the range of dosage mentioned above.

In the case of oral administration, obviously, tablets may also containadditives such as sodium citrate, calcium carbonate and dicalciumphosphate together with various additives such as starch, preferablypotato starch and the like, and binders such as polyvinyl-pyrrolidone,gelatin and the like. It is further possible to add lubricants such asmagnesium stearate, sodium lauryl-sulphate and talc for producingtablets. In the case of aqueous suspensions and/or elixirs which areintended for oral administration, the active ingredient may be usedtogether with various agents for improving the flavor, dyestuffs,emulsifiers and/or diluents, such as water, ethanol, propylene-glycol,glycerol and other compounds or combi nations of this type.

In the case of parenteral administration, there may be used solutions ofthe active ingredients in sesame or peanut oil or in aqueouspropylene-glycol or N,N-dimethyl formamide, as well as sterile aqueoussolutions if the compounds are water-soluble. Such aqueous solutionshould be bufiered in tL: usual manner; if required, and the liquiddiluent should previously be rendered isotonic by the addition of thenecessary amount of salt or glucose. These aqueous solutions areparticularly suitable for intravenous, intramuscular and intraperitonealinjections.

In humans, a dosage of 40 mg./ kg. administered at intervals of 12 hoursresult in a blood level of between and 11 7/ ml. The half-life period inhuman serum in vivo amounts to 6 hours on the average. Up to 30 to 40%of the administered amount of the substance are excreted with the urinein active form. The resorption quota amounts to more than 70% in thecase of oral administration.

The LD for mice, rats, rabbits, dogs and cats lies between about 600 and2200 mg. of the stated compounds/ kg. body weight in the case of oraladministration.

The present invention also includes pharmaceutical compositionscomprising at least one of the N-trityl-imidazoles or salts thereof inadmixture with a solid or liquid diluent or carrier which may be any ofthe conventional diluents or carriers used in pharmaceuticalcompositions.

The present invention also includes unit dosage forms of medicationwhich comprise at least one of the compounds of the present inventioneither alone or in admixture with a solid or liquid diluent or carrier.The compounds of the present application may include a protectiveenvelope or cover containing the active compound within. Unit dosageform means that the composition is in the form of discrete portions,each containing a unit dose or a multiple or sub-multiple of the unitdose of the active ingredient which is the compound of the presentinvention. Such portions may, for example, be in monolithic coherentform, such as tablets, suppositories, pills or dragees; in wrapped orconcealed form, such as wrapped 8 powders, cachets, sachets or capsules,in ampules such as in sterile solution; or in other forms known to theart.

What is claimed is: 1. An antifungal composition useful foradministration to humans and animals, which comprises a therapeuticallyeffective amount of a compound of the formula:

wherein X" is S-lower alkyl, or a pharmaceutically acceptable non-toxicsalt thereof.

4. A method according to claim 3, wherein the compound is 1(p-thiomethylphenyl-diphenyl-methyl)-imidazole.

References Cited UNITED STATES PATENTS 3,321,366 5/1967 Mussell et a1424273 JEROME D. GOLDBERG, Primary Examiner

